1. Field of the Invention
This invention relates to a peptide derived from a vaccinia virus protein. In particular the invention relates to a peptide derived from the vaccinia virus protein A46.
2. Description of Related Art
Pattern recognition receptors (PRRs) are critical for the ability of the innate immune response to detect pathogens. Examples of classes of PRRs include Toll-like receptors (TLRs), RIG-I-like receptors (RLRs) and NOD-like receptors (NLRs). TLRs recognize pathogen-associated molecular patterns (PAMPs) on microorganisms, leading to the activation of signaling pathways and subsequent altered gene expression. This leads to the production of anti-microbial effector cytokines such as the proinflammatory cytokines interleukin-1 (IL-1) and tumour necrosis factor α (TNFα), and the type I interferons (IFNs) IFNα and IFNβ. Specific TLRs have been shown to detect particular PAMPs, for example TLR2 recognises certain bacterial lipopeptides, TLR3 recognises double-stranded (ds) RNA, TLR4 responds to lipopolysaccharide (LPS), TLR7 or TLR8 to ssRNA, and TLR9 to dsDNA containing CpG motifs (Akira et al, 2006).
TLR4 is of particular interest here, and is one of the most important and studied of the TLRs, given its role in mediating the many effects of LPS on cells. Furthermore, TLR4 can respond to a variety of other cellular insults and endogenous danger signals, making it an attractive drug target for therapeutic intervention in the large range of diseases now appreciated to involve inappropriate or aberrant activation of innate immune signaling. Inhibitors of specific innate immune signaling pathways are an attractive strategy in certain disease contexts in order to disable pathways contributing to disease while maintaining some redundant pathogen detection systems. As such, a specific inhibitor of TLR4 would be a valuable asset.
An important example of a role for TLRs in disease processes is that of inflammation. Inflammation is a complex process underlying a large number of acute and chronic diseases such as sepsis, rheumatoid arthritis, multiple sclerosis and colitis. Most therapeutic approaches to blocking inflammation target individual effector cytokines such as TNF, often with good effect. There is now strong evidence that TLRs have a crucial role in initiating both pathogen-induced and sterile inflammation, and as such TLRs provide the initial trigger which ultimately leads to the production of such effector cytokines (O'Neill, 2006). Therefore, targeting the initial intracellular TLR signalling cascades directly is ultimately likely to be an even more effective approach.
TLR4 activators cause it to homodimerise, via its intracellular Toll-IL-1R (TIR) domain. This leads to the engagement of TIR domain-containing adaptor proteins with the receptor complex, namely myeloid differentiation factor 88 (MyD88), MyD88 adaptor-like (Mal, also called TIRAP), TIR domain-containing adaptor inducing IFNβ (TRIF), and TRIF-related adaptor molecule (TRAM). Together, MyD88 and Mal mediate a signaling pathway leading to NFκB and mitogen-activated protein kinase (MAPK) activation, while TRAM and TRIF control a pathway leading to NFκB and IFN regulatory factor (IRF) activation (O'Neill and Bowie, 2007). Other TLRs use different repertoires of TIR adaptors to signal, for example TLR2 utilises MyD88 and Mal, TLR3 utilises only TRIF and TLR9 utilises only MyD88 (O'Neill and Bowie, 2007).
Two vaccinia virus proteins, A46R and A52R, have been identified which can modulate intracellular signalling by TLRs and thus inhibit the TLR-initiated immune response. A52R potently blocks TLR-induced activation of the transcription factor NFκB (a well-known lead drug target) by interacting with the TLR signalling molecule IRAK2 (Harte et al, 2003; Keating et al, 2007). A46 has distinct targets, and can suppress TLR signaling axes utilising MyD88, Mal, TRIF or TRAM, leading to inhibition of MAP kinase, NFκB and IRF3 activation (Stack et al, 2005). This is because A46 has a TIR domain, which allows it to bind to mammalian TIR adaptors (Stack et al, 2005).